D'Amico Gabriela, Lam Francis, Hagen Thilo, Moncada Salvador
Wolfson Institute for Biomedical Research, University College London, UK.
J Cell Sci. 2006 Jun 1;119(Pt 11):2291-8. doi: 10.1242/jcs.02914.
Endogenously produced nitric oxide (NO) interacts with mitochondrial cytochrome c oxidase, leading to inhibition of cellular respiration. This interaction has been shown to have important physiological and pathophysiological consequences. Exogenous carbon monoxide (CO) is also known to inhibit cytochrome c oxidase in vitro; however, it is not clear whether endogenously produced CO can inhibit cellular respiration and, if so, what the significance of this might be. In this study, we show that exogenous CO inhibits respiration in a moderate but persistent manner in HEK293 cells under ambient (21%) oxygen concentrations (K(i) = 1.44 microM). This effect of CO was increased (K(i) = 0.35 microM) by incubation in hypoxic conditions (1% oxygen). Endogenous CO, generated by HEK293 cells transfected with the inducible isoform of haem oxygenase (haem oxygenase-1; HO-1), also inhibited cellular respiration moderately (by 12%) and this was accompanied by inhibition (23%) of cytochrome c oxidase activity. When the cells were incubated in hypoxic conditions during HO-1 induction, the inhibitory effect of CO on cell respiration was markedly increased to 70%. Furthermore, endogenously produced CO was found to be responsible for the respiratory inhibition that occurs in RAW264.7 cells activated in hypoxic conditions with lipopolysaccharide and interferon-gamma, in the presence of N-(iminoethyl)-L-ornithine to prevent the synthesis of NO. Our results indicate that CO contributes significantly to the respiratory inhibition in activated cells, particularly under hypoxic conditions. Inhibition of cell respiration by endogenous CO through its interaction with cytochrome c oxidase might have an important role in inflammatory and hypoxic conditions.
内源性产生的一氧化氮（NO）与线粒体细胞色素c氧化酶相互作用，导致细胞呼吸受到抑制。这种相互作用已被证明具有重要的生理和病理生理后果。外源性一氧化碳（CO）在体外也已知会抑制细胞色素c氧化酶；然而，尚不清楚内源性产生的CO是否能抑制细胞呼吸，如果能，其意义可能是什么。在本研究中，我们表明在环境（21%）氧浓度下，外源性CO以中等但持续的方式抑制HEK293细胞的呼吸（K(i)=1.44 microM）。在低氧条件（1%氧）下孵育可增强CO的这种作用（K(i)=0.35 microM）。用血红素加氧酶（血红素加氧酶-1；HO-1）的可诱导同工型转染的HEK293细胞产生的内源性CO也适度抑制细胞呼吸（12%），同时伴有细胞色素c氧化酶活性的抑制（23%）。当在HO-1诱导期间将细胞置于低氧条件下孵育时，CO对细胞呼吸的抑制作用显著增加至70%。此外，发现在存在N-（亚氨基乙基）-L-鸟氨酸以防止NO合成的情况下，内源性产生的CO是在低氧条件下用脂多糖和干扰素-γ激活的RAW264.7细胞中发生的呼吸抑制的原因。我们的结果表明，CO对活化细胞的呼吸抑制有显著贡献，特别是在低氧条件下。内源性CO通过与细胞色素c氧化酶相互作用抑制细胞呼吸可能在炎症和低氧条件中起重要作用。
